Rationale: Pulmonaryarterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lungmetabolism.Glycolytic metabolismcan be detected with the positron emission tomography (PET) tracer 18F-fluorodeoxyglucose (FDG). Objectives: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. Methods: PAHwas induced in Sprague-Dawley rats bymonocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. Measurements and Main Results: Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regressmedial hypertrophy. Glut1mRNA is up-regulated in both endothelium and PASMCs, but not airway cells ormacrophages. PASMCs frommonocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1α(HIF- 1α), which underlies their glycolytic phenotype. Conclusions: HIF-1α-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.
|Original language||English (US)|
|Number of pages||10|
|Journal||American journal of respiratory and critical care medicine|
|State||Published - Mar 15 2012|
- Glucose transporter-1 (Glut1)
- Hypoxia-inducible factor-1α
- Sugen 5416